Abstract
New target molecules, namely, 2-phenylamino-4-phenoxyquinoline derivatives, were designed using a molecular hybridization approach, which was accomplished by fusing the pharmacophore structures of three currently available drugs: nevirapine, efavirenz, and rilpivirine. The discovery of disubstituted quinoline indicated that the pyridinylamino substituent at the 2-position of quinoline plays an important role in its inhibitory activity against HIV-1 RT. The highly potent HIV-1 RT inhibitors, namely, 4-(2′,6′-dimethyl-4′-formylphenoxy)-2-(5″-cyanopyridin-2″ylamino)quinoline (6b) and 4-(2′,6′-dimethyl-4′-cyanophenoxy)-2-(5″-cyanopyridin-2″ylamino)quinoline (6d) exhibited half-maximal inhibitory concentrations (IC50) of 1.93 and 1.22 µM, respectively, which are similar to that of nevirapine (IC50 = 1.05 µM). The molecular docking results for these two compounds showed that both compounds interacted with Lys101, His235, and Pro236 residues through hydrogen bonding and interacted with Tyr188, Trp229, and Tyr318 residues through π–π stacking in HIV-1 RT. Interestingly, 6b was highly cytotoxic against MOLT-3 (acute lymphoblastic leukemia), HeLA (cervical carcinoma), and HL-60 (promyeloblast) cells with IC50 values of 12.7 ± 1.1, 25.7 ± 0.8, and 20.5 ± 2.1 µM, respectively. However, 6b and 6d had very low and no cytotoxicity, respectively, to-ward normal embryonic lung (MRC-5) cells. Therefore, the synthesis and biological evaluation of 2-phenylamino-4-phenoxyquinoline derivatives can serve as an excellent basis for the development of highly effective anti-HIV-1 and anticancer agents in the near future.
Highlights
Quinoline derivatives are an important class of heterocycles that exist among the principal components of natural products [1,2]
2-Phenylamino-4-phenoxyquinoline derivatives were evaluated via the molecular hybridization approach using the chromophores of HIV-1 reverse transcriptase (RT) inhibitors, namely, NVP, EFV, and RPV. 2,6-Dimethyl-4-formylphenoxy, 2,6-dimethyl-4-cyanophenoxy, and 4-cynophenyl amino were used as substituents in the core structure of quinoline to compare their inhibitory activity against HIV-RT related to the substituents of RPV and ETR in order to prevent unpredictable activity and confirm the potential of the designed compounds
The literature revealed that 2-phenylamino-4phenoxy-quinolines (5a–5d) bind to HIV-1 RT at an identical location and with low binding energy [14]
Summary
Quinoline derivatives are an important class of heterocycles that exist among the principal components of natural products [1,2]. Available first-generation NNRTIs, namely, nevirapine (NVP), delavirdine, and efavirenz (EFV), can directly interfere with HIV-1 RT by binding to an allosteric site in similar positions [9,10]; the rapid emergence of mutant viral strains has severely compromised the clinical use of these HIV-1 RT inhibitors [11]. Diarylpyrimidine derivatives, such as etravirine (ETR, TMC125) and rilpivirine (RPV, TMC278), are second-generation NNRTIs that have been approved by the FDA for clinical use. The substituents in the core structure of quinoline gave insights into the important interactions between the NNRTI-binding pocket and the synthesized compounds, which could provide information for structural improvement based on the molecular design of potent NNRTIs from the molecular docking results
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